Receptor for Advanced Glycation End Products (RAGE) in Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating disease that involves a severe reduction in respiratory function, essentially culminating in the loss of the ability to sufficiently breathe. Current therapies are largely ineffective, and many of the molecular details of the pathogenesis of IPF remain unknown. Thus, new therapeutic targets need to be identified.We investigated a possible role for the receptor for advanced glycation end products (RAGE) in the pathogenesis of IPF. RAGE is a multiligand member of the immunoglobulin superfamily of cell surface receptors. It is generally associated with cellular perturbation in that RAGE-ligand interactions initiate a signaling cascade that ends with the activation of the pro-inflammatory transcription factor NF-kappaB. In most adult healthy tissues RAGE is expressed at low levels, but it is highly upregulated at sites of various pathologies, where it is thought to act as a propagation factor for disease. Notably, the exception to low RAGE expression in healthy adult tissues is the lung, the organ shown to have the highest RAGE transcript levels in humans and rats. This suggests that RAGE may have a role in lung homeostasis, implying that RAGE serves a function in the lung distinct from that in other tissues.RAGE has a secreted isoform, sRAGE, that acts as a decoy receptor. In humans, sRAGE is a product of alternative splicing. In contrast, we found that sRAGE in mice is produced by proteolytic truncation of cell surface RAGE. The focus of this project was to investigate the hypotheses that RAGE and sRAGE regulation are altered during the pathogenesis of pulmonary fibrosis, and that this alteration is a key step in the pathogenesis of pulmonary fibrosis. To address these hypotheses, we utilized the bleomycin and asbestos mouse models of pulmonary fibrosis as well as human IPF tissues. We found that in both animal models and in IPF tissues, RAGE and sRAGE protein levels are significantly reduced during the pathogenesis of pulmonary fibrosis. Observations from RAGE knockout mice suggest that absence of pulmonary RAGE is itself pro-fibrotic. These studies reveal RAGE as a novel therapeutic target in the pathogenesis of idiopathic pulmonary fibrosis